(A) Field of the Invention
This invention is related to an improved preparation of 5-pyridinyl-6-R.sub.2 -3-R.sub.1 -2(1H)pyridinones and to intermediates used therein.
(B) Description of the Prior Art
Some of compounds I, IV and V are described as cardiotonically active drugs (U.S. Pat. No. 4,107,315; Ger. Offen. No. 3944568, etc.) and was prepared by condensating under classical conditions, preferred by employing sodium methoxide in methanol or dimethylformamide with only low to moderate yields and in a drastic basic media.
The present specification relates to a novel process for preparing 5-pyridyl pyridine-2(1H)-ones of general formula I ##STR1## in which R.sub.1 is an amino group, R.sub.2 a hydrogen atom or a lower alkyl group and R.sub.3 is a 4-, 3- or 2-pyridyl group as well as the intermediates used in its preparation.
Some of the compounds referred to this invention have shown to be effective as antidysrhythmic agents, and also some of them are useful intermediates in the preparation of other derivatives with the therapeutic activity mentioned.
According to this invention the compounds of general formula I are prepared through several steps from the pyridyl derivatives of general formula II as it is depicted in the next scheme: ##STR2## The first step comprises reacting a compound of general formula II, where R.sub.2 and R.sub.3 have the meanings given above, with an excess of malonamide, both dissolved in a suitable solvent, such as chloroform, methylene chloride, acetonitrile, dimethylformamide, etc., in the presence of a molar excess of a finely ground alkali metal, alkaline-earth metal carbonate, bicarbonate or hydroxide and a quaternary ammonium or phosphonium salt which performs as a phase-transfer catalyst (PTC). This process may be suitably conducted at a temperature within the range of about 20.degree. to 160.degree. C., continuously stirred at a rate higher than 200 r.p.m. and for a period within the range of about 24 to 72 hours to afford compounds of general formula IV which can be purified by recrystallization from a suitable solvent, although this is not necessary for them to be used in the next step.
The compounds of general formula IV can also be prepared by treatment of a compound of general formula II, where R.sub.2 and R.sub.3 have the meanings given above, with cyanoacetamide in a suitable solvent such as chloroform, methylene chloride, acetonitrile, dimethylformamide, etc., in the presence of a molar excess of a finely ground alkali metal, alkaline-earth metal carbonate, bicarbonate or hydroxide and a quaternary ammonium or phosphonium sal which performs as a phase-transfer catalyst. This process may be suitably conducted at a temperature within the range of about 10.degree. to 160.degree. C., continuously stirred at a rate higher than 200 r.p.m. and for a period within the range of about 2 to 36 hours to afford 3-cyano-pyridine-2(1H)-ones of general formula III, where R.sub.2 and R.sub.3 have the meanings given above. These compounds can be purified by recrystallization from a suitable solvent, although this is not necessary to carry on with the synthesis. In a second step, the cyano group of this compounds is partially hydrolyzed to a carbamoyl group following the usual procedures to afford the derivatives of general formula IV, where R.sub.2 and R.sub.3 have the meanings given above.
In the second step of the reaction the carboxamide of general formula IV leads to the corresponding primary amine following the usual procedures, for example by treatment with an alkaline hypohalide [Org. React., 3, 267(1946)], by the action of hydrazine and further nitrosation and heat [Org. React., 3, 337(1946)], etc., affording the title derivatives of general formula I which are purified by crystallization from a suitable solvent.
The following examples ilustrate the processes used for preparing the 5-pyridyl pyridine-2(1H)-ones, and are not intended to limit the scope of this invention.